Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

• British Patent Application 03892/76-19002/76 discloses thioether derivatives of clavulanic acid, pharmaceutical compositions containing them and a process for their preparation.
• the disclosed process comprised the reaction of an ester of clavulanic acid with a thiol and thereafter if desired converting the thus formed ester of the thioether into the corresponding free acid or its salt.
• the process disclosed is very versatile leading to the preparation of a wide class of thioethers it suffers from the disadvantage of giving only relatively poor yields.
• the later French Published Patent Application No. 2,342,292 also discloses the preparation of thioethers of clavulanic acid by the reaction of a sulphur nucleophile with an ester of 9-halo or 9-acyloxydeoxyclavulanic acid.
• a synthesis has now been found that has the advantage that it may be carried out at ambient temperature if desired, does not involve the use of foul smelling thiols at the coupling stage but instead employs easily weighable, solid sulfenimide intermediates.
• the intermediates used in this process are also conveniently accessible and used, for example by the methods of M.Behforouz and J.E. Kenwood, J. Org. Chem., 34, 51 (1969) or K.A.M. Walker, Tet. Lett., 4475 (1977).
• the use of this process for preparing aryl thioethers offers the further advantage of particularly good yields.
• the present invention provides a process for the preparation of thioether derivatives of deoxyclavulanic acid of the formula (I): wherein R 1 is the residue of a thiolR 1 SH and R 2 is a group such that C0 2 R 2 represents a carboxylic acid moiety or a salt or ester thereof; which process comprises the reaction of a compound of the formula (II): with a compound of the formula (III): and a compound of the formula (IV): in which compounds R 1 is as defined in relation to formula (I); R 3 and R 4 are moieties such that the compound of the formula (II) is a sulfenimide; R 5 is a group such that the compound of the formula (III) is an ester of clavulanic acid; and R 6 , R 7 and R 8 are groups such that the compound of the formula (IV) is a phosphine; and thereafter if desired converting the thus formed compound of the formula (I) wherein R 2 is a group such that C0
• Suitable groups R include hydrocarbon groups and hydrocarbon groups substituted by a group of the sub-formulae OR 9 , O.CO.R 9 , C O.R 9 , C0 2 R 9 , NH.C O .R 9 , NR 10 .COR 9 and NR 10 CO 2 R 9 wherein R 9 is a. lower alkyl group or lower aralkyl group and R 10 is a lower alkyl group.
• hydrocarbon includes alkyl, alkenyl, phenyl and phenylalkyl groups.
• lower means that the group contains up to 4 carbon atoms.
• aralkyl means a lower alkyl group substituted by a phenyl group.
• R include the methyl, ethyl, n-propyl, n-butyl, phenyl, benzyl, allyl, 2-methoxyethyl, 4-methoxyphenyl, 4-methoxybenzyl and the like.
• Preferred groups R 1 include optionally substituted phenyl groups.
• R are optionally substituted aromatic heterocyclic groups, such as pyridyl, furyl, thienyl and the like.
• R 1 is an optionally substituted aromatic group.
• Suitable groups -CO 2 R 2 include those of the sub-formulae -CO 2 A 1 or -C0 2 CHA 2 A 3 wherein A is a lower alkyl group optionally substituted by a group OA 4 , O.CO.A 4 or O.CO.O.A 4 wherein A 4 is a lower alkyl or phenyl group; A 2 is a lower alkenyl, lower alkynyl, phenyl group or phenyl group substituted by a halogen atom or nitro, A 5 , OA 5 or O.CO.A 5 group where A 5 is a lower alkyl group; and A3 is a hydrogen atom or a phenyl group or a phenyl group substituted by a halogen atom or a nitro, A 5 , O A 5 or O.CO.A 5 group where A 5 is a lower alkyl group; or -CHA 2 A 3 represents a phthalidyl group.
• the -C0 2 R 2 group is one readily cleaved by mild base, for example a lower alkyl or lower alkoxymethyl group.
• the -C0 2 R 2 group is one readily cleaved by hydrogenolysis, for example a benzyl group optionally substituted by a halogen atom or a nitro, A 5 , OA 5 or O.CO.A 5 group where A 5 is a lower alkyl group.
• a benzyl group optionally substituted by a halogen atom or a nitro, A 5 , OA 5 or O.CO.A 5 group where A 5 is a lower alkyl group.
• the benzyl, p-methoxybenzyl and p-nitrobenzyl group are particularly favoured.
• the groups R 3 and R 4 will normally be selected from hydrocarbon groups which may be linked together. Particularly apt groups R 3 and R 4 include lower alkyl groups optionally linked to form part of a 5- or 6- membered ring.
• Preferred compounds of the formula (II) include those of the formulae (V) and (VI): wherein R 1 is as defined in relation to formula (I).
• the compounds of the formula (V) are particularly suitable as a by-product of the reaction is water-soluble and may thus be readily removed by washing with water.
• Suitable values for R 6 , R 7 and R 8 include hydrocarbon groups of up to 7 carbon atoms and hydrocarbon groups substituted by a group of the sub-formulae OR 11 or O.CO.R 11 where R 11 is a lower alkyl group.
• R 6 , R 7 and R 8 each have the same meaning.
• R 6 , R 7 and R 8 include methyl, ethyl, n-propyl, n-butyl, phenyl, 4-methoxyphenyl and benzyl.
• a particularly suitable compound of the formula (IV) is tri-n-butyl-phosphine.
• the reaction of the compounds of the formulae (II), (III) and (IV), may take place at any convenient non- extreme temperature, for example -10°C to 50 o C, more usually 0° to 40°C, generally 10° to 30°C and very conveniently at ambient (about 15-25°C).
• the reaction is generally carried out in an aprotic medium.
• Suitable solvents include hydrocarbon solvents such as benzene, toluene and the like.
• reaction may be carried out under an inert gas such as nitrogen.
• the mixture may be washed with water to remove the water-soluble products, and the organic layer dried and evaporated.
• the initial product may be further purified by chromatography if desired, for example over silica eluting with ethyl acetate/petroleum ether or the like.
• ester of the thioether may be converted to the corresponding acid or salt in conventional manner, for example as described in Belgian Patent No. 847045.
• N-(pyrid-4-ylthio) succinimide (0.100g,0.48 mmole) was added to a solution of tri-n-butylphosphine (0.118ml, 0.48 mmole) in THF (5ml) under nitrogen and stirred 5 minutes.
• p-Nitrobenzyl clavulanate (0.100g,0.30 mmole) was added and stirring continued for 30 minutes.
• the solution was diluted with ethyl acetate (30 ml), washed with water (2 x 20 ml), dried over MgS0 4 and evaporated.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

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Family Applications (1)

Country Status (4)

Citations (1)

• 1979
  • 1979-05-08 EP EP79300779A patent/EP0005914A1/fr not_active Withdrawn
  • 1979-05-15 CA CA327,655A patent/CA1126733A/fr not_active Expired
  • 1979-05-26 JP JP6550779A patent/JPS54157597A/ja active Pending
  • 1979-05-30 ES ES481098A patent/ES481098A1/es not_active Expired

Patent Citations (1)

Non-Patent Citations (2)

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